Saint Louis University

School of Medicine
School Year 2015-2016

A Report Presented
To the Faculty of the School of Medicine
Department of Biochemistry

Finals Module 1

Group 6:
Beray, Brandon Jayle W.
Bugtong, Wilbert V.
Verdadero, Ryan Louis M.
Carlos, Erica Chloe D.
Facun, Angeli Eleanor B.
Malinit, Tricia Michaela L.
Sab-it, Audrey K.

April 23, 2016

CASE 1

A 2 year old girl is admitted to the pediatric ward owing to an increase in

abdominal girth and failure to thrive. She was breast-fed until one year of age, at
which time her mother ran out of milk. She is apathetic and irritable and has been
having frequent episodes of diarrhea. Physical examination reveals her height and
weight to be in the fifth percentile, skin and hair depigmentation, thinning of hair,
dry skin, and hyperkeratosis on the axillae and groin. There is hepatomegaly and
ascites, generalized pitting edema, loss of muscle, and lethargy. CBC reveals
anemia and lymphopenia. Laboratory tests also reveal hypoalbuminemia,
hypokalemia, and hypomagnesemia.

QUESTIONS:
1. What is the most likely diagnosis? Justify your answer.

The most likely diagnosis is Kwashiorkor, a form of protein-energy

malnutrition (PEM) that occurs when protein deprivation is relatively greater than
the reduction in total calories. Comparisons of Kwashiorkors signs and symptoms
and patients manifested signs and symptoms are tabulated below:

Patients manifested signs and

Kwashiorkors signs and symptoms
symptoms

Stunted growth Height and weight to be in the fifth

percentile

Edema Generalized pitting edema

Skin lesions Skin depigmentation, dry skin,

hyperkeratosis on the axillae and groin

Depigmented hair Hair depigmentation, thinning of hair

Enlarged fatty liver Hepatomegaly and ascites

Decreased plasma Albumin

Hypoalbuminemia
concentration

Muscle loss Loss of muscle

Severe diarrhea
Frequent episodes of diarrhea

irritability (excessive response to a

Apathetic and irritable
stimulus)
lethargy (fatigue) (early sign) or mental
apathy (lack of feeling or emotion) Lethargy
Frequently seen in:

Diet consists predominantly of

carbohydrates

breast-fed until one year of age Breast-fed until one year of age

2. What is the biochemical basis?

Kwashiorkor, involves protein malnutrition, hence the patient is lacking in
essential amino acids needed by the body for different anabolic and catabolic
reactions. As a consequence of protein deficiency in the diet, amino acids available
for the synthesis of liver proteins are highly decreased. In that case then there is a
decrease in the synthesis of albumin and apolipoproteins; leading to
hypoalbuminemia. As a result of the hypoalbuminemia, the colloid osmotic pressure
in the body is altered. As a result of the lack of albumin, no substantial pressure
gradient can be established to draw fluids from the tissue back into the
bloodstream, causing the fluids to pool causing the swelling and distention of the
abdomen. This is the main reason also as to why edema is evident at the childs
extremities.
The depigmentation occurring in the integument of the patient is explained
by the lack of the amino acid tyrosine. Tyrosine is a precursor for the synthesis of
melanin, thus a lack of it would obviously lead to decreased protein synthesis;
leading to the depigmentation.
It is also important to note that some proteins are precursors for
neurotransmitters (e.g. tryptophan is a precursor for serotonin; and tyrosine for
dopamine). Thus their synthesis is also affected in protein deficiency which might
explain the neurological problem involved with the child.
We must not also neglect the fact that the child is lacking in essential amino
acids, thus the function that each of the amino acids perform is impaired. For
example, leucine is essential in increasing muscle mass. Hence a lack of it
contributes to the loss of muscle mass in our patient. The patients condition is also
associated with atrophy of the mucosa of the bowels, hence explaining the patients
bout with diarrhea. In conclusion, the lack of protein diet in our patient, leads to the
deficiency of amino acids needed for different biochemical reactions, leading to the
patients condition.
References:
Marshall, William; Marta Lapsey; Andrew Day; and Ruth Ayling. 2014. Clinical
Biochemistry. 3rd edition. Toronto: Elsivier Limited. Page 201
Medina, Marco; Claudia Amador, Rebecca Toranzo, Heike Hesse, Kenton Holden, Ana
Ortiz, Luis Salinas. 2008. Neurologic Consequences of Malnutrition. New York: World
Federation of Neurology. Page 25
Conley, Travis. 2012. The function of Essential amino acids and the human body.
http://www.ocdoct.com/the-function-of-essential-amino-acids-and-the-human-body/

CASE 2:
1. What is the most likely diagnosis? Justify the answer.

The most likely diagnosis for the case is pernicious anemia. The table below shows a
comparison of the classic signs and symptoms of pernicious anemia and the
manifestations of the patient.

Classic Signs and Symptoms of Patient Manifestations

Pernicious Anemia
Peripheral blood smear: Macrocytic
anemia with mild leukopenia and
thrombocytopenia
Low serum cobalamin levels
Abnormal mentation and
deterioration of vision and hearing
Achlorydic
Positive Schilling test
Feeling tired and weak
Loss of appetite
Tingling and numbness in hands
and feet
Beefy, red, smooth tongue
Low-grade fever and mild icterus
Elevated bilirubin
Severe anemia, dyspnea,
tachypnea and evidence of
congestive heart failure
Liver may be enlarged
Splenic tip is palpable
Macrocytic hypochromic anemia,
leukopenia with hypersegmented
neutrophils and thrombocytopenia
Low blood vitamin B12 levels
Loss of balance, vibratory and
position sense in both lower
extremities
Achlorydia
Positive Schilling test
Weakness, dizziness and nausea
Anorexia
Numbness and tingling in the
extremities
Smooth beefy-red tongue
Slightly icteric eyes
Elevated bilirubin
Shortness of breath
Hepatosplenomegaly

2. Explain the biochemical basis of the patients condition.

Classic pernicious anemia is caused by the failure of gastric parietal cells to
produce sufficient IF (a gastric protein secreted by parietal cells) to permit the
absorption of adequate quantities of dietary vitamin B-12. Other disorders that
interfere with the absorption and metabolism of vitamin B12 can produce cobalamin
deficiency, with the development of a macrocytic anemia and neurologic
complications.

The basic structure known as vitamin B12 is solely synthesized by

microorganisms, but most animals are capable of converting vitamin B12 into the
two coenzyme forms, adenosylcobalamin and methylcobalamin. The former is
required for conversion of L- methylmalonic acid to succinyl coenzyme A (CoA), and
the latter acts as a methyltransferase for conversion of homocysteine to
methionine.

When either cobalamin or folate is deficient, thymidine synthase function is

impaired. This leads to megaloblastic changes in all rapidly dividing cells because
DNA synthesis is diminished. In erythroid precursors, macrocytosis and ineffective
erythropoiesis occur. Dietary cobalamin is acquired mostly from meat and milk and
is absorbed in a series of steps, which require proteolytic release from foodstuffs
and binding to IF. Subsequently, recognition of the IF-cobalamin complex by
specialized ileal receptorscubilin receptorsmust occur for transport into the
portal circulation to be bound by transcobalamin II (TCII), which serves as the
plasma transporter. The cobalamin-TCII complex binds to cell surfaces and is
endocytosed. The transcobalamin is degraded within a lysozyme, and the cobalamin
is released into the cytoplasm. An enzyme-mediated reduction of the cobalt occurs
with either cytoplasmic methylation to form methylcobalamin or mitochondrial
adenosylation to form adenosylcobalamin. Defects of these steps produce
manifestations of cobalamin dysfunction.

Reference:
Schick, P., et al. Pernicious Anemia. Medscape

CASE 3:
A 9 month old female is brought to the pediatric clinic because of listlessness and
anorexia. She is the daughter of an unemployed poor urban couple and has never
before seen a pediatrician or taken any medication. Her parent's report a diet of
unsupplemented cow's milk.
Physical examination reveals weakness, pallor, hyperkeratosis and hemorrhagic
perifolliculitis of the skin of the lower extremities, forearms, and abdomen. There
are purpuric skin rashes, splinter hemorrhages in the nail beds of the hands,
tenderness and swelling of the distal femur and costochondral junctions. There are
bleeding gums, and petechiae are seen over the nasal and oral mucosa. The CBC
reveals microcytic, hypochromic anemia, and leukopenia. Plasma and platelet levels
of ascorbic acid are low. The bleeding time is prolonged.
X-rays show sub periosteal hemorrhages, both legs and knees show "ground glass"
appearance of bones and epiphyses.
QUESTIONS
1. What is the most likely diagnosis? Justify your answer.
Diagnosis: Infantile Scurvy (Moeller's Disease) secondary to reduced
dietary intake of Vitamin C
To consider: Possible Clotting factor deficiencies
Justification:

Classical signs and symptoms of Signs and symptoms manifested by

 Scurvy the patient
Low levels of Serum Ascorbic Acid Low levels of Serum Ascorbic Acid
Hemorrhage or Bleeding Problems Hemorrhagic Perifolliculitis
Purpuric skin rashes
Splinter hemorrhages in the nail
beds of the hands
Bleeding gums
Petechiae are seen over the nasal
and oral mucosa.
Subperiosteal Hemorrhages
Hyperkeratosis Hyperkeratosis
Hypochondriasis Not manifested
Hematologic Abnormalities: Anemia Microcytic, hypochromic anemia,
and leukopenia
Pallor
Prolonged Bleeding Time Prolonged Bleeding Time
Lethargy, Weakness Lethargy, Weakness
Poor Weight Gain, Anorexia Anorexia
Bone formation abnormalities X-ray: Ground glass" appearance of
bones and epiphyses.
Long Bones are commonly involved Tenderness and swelling of the distal
femur and costochondral junctions.

2. Explain of the biochemical basis of the patients condition.

The patient has Infantile Scurvy. The disease is caused by a deficiency of
Vitamin C, or ascorbate. Ascorbate plays a critical role in several biochemical
pathways, particularly in the synthesis of collagen. One of the main functions of
ascorbate is protein hydroxylation (Teal, 1997). Protein hydroxylation is a post-
translational modification in which a hydroxyl group is added to a protein residue.
Protein hydroxylation is involved in the maturation of collagen. Without ascorbate,
collagen is not hydroxylated and the collagen molecule is structurally unstable
(Szarka, 2013). Ascorbate is also directly involved in the biosynthetic pathway of
carnitine (Asard, 2004). Impaired synthesis of carnitine, along with collagen, results
in the common symptoms of scurvy.
Ascorbate is required for the function of some hydrolases. Hydrolases
catalayze protein hydroxylation in two major steps. In the first step, the protein
residue is hydroxylated by the hydrolase and 2-oxoglutarate is decarboxylated.
During the next step, ferrous iron is oxidized and the hydrolase becomes
catalytically inactive. Ascorbate is required to reduce iron and render hydrolase
catalytically active again. Dithreitol and cysteine can be used to reduce the iron but
the reaction rate is significantly lower than that of ascorbate. An example of a
hydrolase that requires ascorbate is collagen prolyl 4-hydroxylase (C-P4H). C-P4H
hydroxylates a proline residue on procollagen to form heat stable collagen (Szarka,
2013).
 In addition to affecting protein hydroxylation, ascorbate is necessary for
carnitine synthesis. Carnitine is an important metabolite that transports fatty acids
into the mitochondria so that they can undergo -oxidation. Ascorbate is utilized by
two different enzymes in the carnitine biosynthetic pathway, -trimethyl-lysine
dioxygenase and -butyrobetaine dioxygenase. Without ascorbate, production of
carnitine declines (Asard, 2004).
Synthesis of Carnitine:

Symptoms of scurvy often take months to develop. One of the first symptoms
is fatigue. Fatigue is linked to decreased production of carnitine. Other symptoms,
such as rotten or loose teeth, rigid tendons, and cartilage fraility, result from less
active prolyl/lysyl hydroxylase. Symptoms associated with loss of prolyl/lysyl
hydroxylase function tend to appear later than fatigue. The difference in the onset
of symptoms could be due to different affinities for ascorbate by the enzymes. The
hydrolases have a higher affinity for ascorbate whereas the dioxygenases have a
lower affinity for ascorbate. Dioxygenases require higher levels of ascorbate to
function (Asard, 2004). As scurvy progresses, the function of dioxygenases
decreases first so fatigue is often one of the first symptoms.
Folic acid (vitamin B9) works with vitamin B12 and vitamin C to help the body
break down, use, and make new proteins. The vitamin helps form red and white
blood cells. It also helps produce DNA, the building block of the human body, which
carries genetic information. Lack of folic acid causes complications like
leukocytopenia and anemia.
Megaloblastic anemia in scurvy has been deemed to result from dietary
deficiency of folate derivatives or to impairment of folate metabolism in the
presence of ascorbic acid deficiency. The hematological response of the
megaloblastic anemia in a patient with scurvy to 5-formyl tetrahydrofolic acid by
mouth together with identification of type of folate excreted in the urine. The
anemia of scurvy is caused in part by the removal of tetrahydrofolates from the
metabolic pool due to the rapid and irreversible oxidation to lO-formyl folic acid. An
important role of ascorbic acid in human metabolism is to prevent oxidation of the
tetrahydrofolates and thus keep the folate metabolism pool in action.
Scurvy can be treated by Vitamin C supplements. Symptoms typically begin
to improve within 24 hours of receiving Vitamin C supplements. Most of the
symptoms of scurvy are reversible. While scurvy mostly occurs in underdeveloped
countries where fresh fruits and vegetables are not accessible, scurvy also occurs in
developed countries (Ngan, 2013). Several metabolic pathways rely on ascorbate so
it is important to eat plenty of fresh produce to obtain the necessary amount of
Vitamin C.

References:
Asard, H., May, J.M., & Smirnoff, N. (Eds.). (2004). Vitamin C: Its Functions and
Biochemistry in Animals and Plants. New York, NY: Garland Science/BIOS Scientific
Publishers.
Goebel, L. (2015, September 23). Scurvy Clinical Presentation. Retrieved from
Medscape: http://emedicine.medscape.com/article/125350-clinical

Harvey, R. A., & Ferrier, D. R. (2011). Lippincotts Illustrated Reviews: Biochemistry

(Fifth ed.). Philadelphia, PA 19103: Lippincott Williams & Wilkins.

Ngan, V. (2013, December 29). Scurvy. Retrieved

fromhttp://dermnetnz.org/systemic/scurvy.html.
Szarka, A. & Lrincz, T. (2013). The role of ascorbate in protein folding. Protoplasma.
Teal, A.R. & Saggers, B.A. (1997). Biochemical Basis of Disease. London: The
Biochemical Society.
http://www.archivesofpathology.org/doi/pdf/10.5858/arpa.2012.0013-RS
https://courtneymckernan.wordpress.com/2014/03/19/biochemistry-of-scurvy/
CASE 4:
A 27-year-old male visits your clinic complaining of diminished visual acuity,
primarily at night. The patient is a political prisoner who has just been released from
incarceration. His vital signs are normal. Physical examination reveals diminished
tear lubrication with dryness, as well as keratinization and corneal ulcers.
Questions:
1. What is the most likely diagnosis? Justify your answer.
Xerophthalmia Signs and Patients Signs and Symptoms
Symptoms
Night blindness Diminished visual acuity at night
Dryness of the conjunctiva and Diminished tear lubrication with
cornea dryness
Keratin formation in the eyes Keratinization
Corneal Ulceration Corneal Ulcers

Based on the signs and symptoms manifested by the patient, it can be

concluded that he is suffering from a condition called Xerophthalmia, which is
observable in patients with severe Vitamin A deficiency. The ultimate sign which
implies its severity, is the formation of corneal ulcerations. The ulceration is caused
by the persistent dryness of the conjunctiva and cornea. Prolonged ulceration may
lead to scaring which will eventually lead to blindness.

2. Explain the biochemical basis of the patients condition.

Retinol, which is commonly known as Vitamin A, is a primary alcohol
containing a beta-ionone ring with an unsaturated side chain. Retinol is oxidized to
form an aldehyde know as retinal. Retinal will undergo further oxidation, which will
yield retinoic acid. Retinoic acid will bind with specific proteins localized in the
nucleus of target tissues, such as epithelial cells. When a retinoic acid-receptor
complex is formed, it will interact with nuclear chromatin to regulate retinoid-
specific RNA synthesis. This interaction results in the control of the production of
specific proteins that mediate several physiologic functions.
One of the important cycles that Vitamin A participates in is the visual cycle.
Rhodopsin, the visual pigment of rod cells in the retina, consists of 11-cis retinal, a
vitamin A derivative. The protein part of this receptor, opsin, contains retinal. Upon
light stimulation, isomerization occurs and results to release of all-trans retinal and
opsin. This mediates the nerve impulse to the brain. Without the impulses to the
brain, there would be increased visual threshold, making it harder for the person to
see in times when it is dim.

The patient in this case, has night blindness, which is an immediate sign of
vitamin A deficiency. This arises from the increased visual threshold making it
difficult to see during dim situations such as nighttime. Since vitamin A is essential
for normal differentiation of epithelial tissues and mucus secretion, prolonged
deficiency will also cause the decline of the two functions mentioned above.
Xerophthalmia is a manifestation of the two impaired functions, which are
decreased differentiation of epithelial tissues and decreased mucus secretion. This
will lead to pathologic dryness of the conjunctiva and cornea. This results in corneal
ulceration, the result of prolonged insufficiency of vitamin A in the diet.

References:
Harvey, R., & Ferrier, D. (2011). Lippincott's Illustrated Reviews: Biochemistry.

Philadelphia, Pennsylvania, USA: Lippincott Williams & Wilkins.

Koolman, J., & Roehm, K.-H. (2005). Color Atlas of Biochemistry. Stuttgart, Germany:

George Thieme Verlag.